The ultimate goal of immunotherapy in autoimmune diseases is to find immunologically specific, relatively non-toxic forms of therapy. Our understanding of the immunopathogenesis of T cell mediated autoimmune diseases implicates T cell activation as an important step in their pathogenesis. The CD28-B7 pathway of T cell costimulation plays a role in the pathogenesis of many T cell mediated autoimmune diseases as demonstrated by disease prevention after blocking this pathway in animal models. In experimental autoimmune encephalomyelitis (EAE) the animal model of MS, CTLA4Ig prevent disease and inhibits relapses. In a model of spontaneous diabetes (the NOD mouse) CTLA4Ig prevents the onset of diabetes. CTLA4Ig has shown effectiveness in a phase I clinical trial of psoriasis and more recently in clinical trials of rheumatoid arthritis. It is currently in clinical trials for multiple sclerosis (MS). It is likely that to achieve tolerance in autoimmune disease, one must target more than one pathway of immune activation. Data obtained from animal models of transplantation suggest that a combination of costimulatory signal blockade and rapamycin can induce long term tolerance. Thus, our primary objective in this project is to study the safety and efficacy of CTLA4Ig treatment in patients with new onset type I diabetes, and the safety and efficacy of CTLA4Ig + rapamycin in patients with the earliest manifestations of multiple sclerosis. The outcome measures for the diabetes trial are safety and metabolic and immune effects of CTLA4Ig therapy. For the MS trial, we will compare the safety and efficacy of CTLA4Ig, rapamycin, and CTLA4Ig+rapamycin, to placebo in patients with clinically isolated syndrome of demyelination. The outcome measures are safety and the development of MS by McDonald criteria. Our group also has the interest and patient populations to participate in clinical trials of psoriasis. The Dermatology Clinical Investigations Unit (DCIU) of Massachusetts General Hospital is an established clinical trials unit with extensive experience. Current and past investigations include five trials of systemic medications in psoriasis similar to those we anticipate studying in trials associated with the ACE. In summary, this proposal encompasses 3 autoimmune diseases: MS, type I diabetes, and psoriasis. We are submitting clinical trial proposals for MS and diabetes with a particular focus on T cell activation pathways. We believe that the interactions among investigators from different clinical specialties will foster new ideas and cross-fertilization leading to better treatment for autoimmune diseases.